Sustained release dosage form of phenothiazine derivatives containing channelizer

ABSTRACT

Once a day sustained release solid oral dosage form of phenothiazine derivative preferably the dibenzothiazepine derivative and their pharmaceutically acceptable salts comprising of a channelizer, rate controlling polymer and suitable pharmaceutically acceptable excipients. The formulation of the present invention is in the form of tablet or capsule which provides a sustained drug action upto 24 hours upon single dose administration.

FIELD OF THE INVENTION

The present invention relates to novel solid oral pharmaceuticalformulation, more particularly sustained release formulation ofantipsychotic drug like phenothiazine derivative. The preferablephenothiazine derivatives in the formulation of the present inventionare heterocyclic analogue of phenothiazines, more preferablydibenzazepine derivative and most preferably the dibenzothiazepinecompounds like quetiapine and pharmaceutically acceptable salt thereof,along with a channelizer which facilitates the release of activepharmaceutical ingredient from the dosage form. This dosage form is asolid oral dosage form which maintains an effective plasma drugconcentration over an extended period of time and thereby provides asustained drug action.

BACKGROUND

Antipsychotic drugs are primarily used to treat psychotropic disordersand other mental and emotional conditions.

Phenothiazines are a class of antipsychotic drugs used for the treatmentof serious mental and emotional disorders, including schizophrenia.

Phenothiazine derivatives include, aliphatic and piperidinephenothiazines (e.g. chlorpromazine, triflupromazine, promazine,mesoridazine, perphenazine etc.), piperazine phenothiazines (e.g.prochlorperazine, fluphenazine, trifluperazine etc.) and heterocyclicanalogues of phenothiazines.

Heterocyclic analogue of phenothiazines include thioxanthenes (e.g.thiothixene), arylbutylpiperidines (including fluorobutyrophenone e.g.haloperidol, and diarylbutylpiperidine e.g. pimozide), dihydroindolones(e.g. molindone hydrochloride), benzisoxazoles (e.g. risperidone) anddibenzazepines.

The dibenzazepines includes dibenzoxazepine (e.g. loxapine),dibenzodiazepine (e.g. clozapine), and dibenzothiazepine (e.g.quetiapine).

U.S. Pat. No. 4,879,288 describes the compound11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepine as a novel antipsychotic drug of classdibenzothiazepine suitable for various psychotropic disorders and havingless side effects. It is commonly known as quetiapine and is used forthe treatment of psychotropic disorders like schizophrenia and acutemanic episodes associated with bipolar I disorder.

Quetiapine is an antagonist at multiple neurotransmitter receptors inthe brain like serotonin type 1 and 2 (5HT_(1A), 5HT₂), dopamine type 1and 2 (D₁, D₂), histamine (H₁) and adrenergic α₁ and α₂ receptors withhigh affinity for serotonin type-2 (5HT₂) and dopamine type-2 (D₂)receptors.

Sustained release solid oral dosage form of the phenothiazinesderivatives is a desired approach in the treatment of psychotropicdisorders. The sustained release formulation avoids frequentadministration of the medicament while maintaining a uniform andconstant release rate of the active pharmaceutical ingredient over anextended period of time.

An effective dissolution profile to maintain effective plasma drugconcentration and controlled release rate of medicament after a solidoral drug administration is another reason to formulate sustainedrelease composition of phenothiazine derivatives drugs preferably thedibenzothiazepine compound like quetiapine.

This aim has been attained in the present invention by using achannelizer in the dosage form along with the active pharmaceuticalingredient, rate controlling polymer and optionally otherpharmaceutically acceptable excipients. The channelizer acts as a poreforming agent and thereby facilitates release of active pharmaceuticalingredient from the dosage form through the pores and helps the ratecontrolling polymer to maintain the desired blood plasma concentrationof the drug over a prolonged period of time and thereby causing asustained action of the drug.

PRIOR ART

WO2005041935 discloses a sustained release solid dosage formulationcomprising a matrix, wherein the matrix comprises a therapeuticallyeffective amount of quetiapine or a pharmaceutically acceptable saltthereof, and a wax material.

WO9745124 discloses a sustained release formulation comprising a gellingagent and quetiapine or a pharmaceutically acceptable salt thereof,together with one or more pharmaceutically acceptable excipients. Thegelling agent is hydroxypropyl methyl cellulose and pharmaceuticallyacceptable excipient is selected from the group consisting ofmicrocrystalline cellulose, lactose, magnesium stearate, sodium citrateand povidone, wherein sodium citrate is a pH modifier.

WO0121179 discloses a granule formulation comprising quetiapine or apharmaceutically acceptable salt thereof and a freely or verywater-soluble binder. The granules is dissolved or suspended in a kitcomprising an aqueous medium and then used for central nervous systemdisorders.

WO03039516 discloses a method for improving dissolution of a poorlydispersible medicament like quetiapine, which comprises mixing thepoorly dispersible medicament with a floating agent and/or a surfactantand granulating the mixture.

OBJECT OF THE INVENTION

It is an object of this invention to provide a sustained release orallyadministrable solid dosage formulation comprising an anti-psychotic drugand pharmaceutically acceptable salt thereof with a channelizer.

It is yet another object of this invention to develop sustained releasesolid oral dosage formulation of phenothiazine derivative, preferablythe heterocyclic analogue of phenothiazine, more preferably thedibenzazepine derivative and most preferably the dibenzothiazepinecompound like quetiapine and pharmaceutically acceptable salt thereof.

One more object of this invention is to prepare a sustained releasesolid oral dosage formulation of phenothiazine derivative andpharmaceutically acceptable salt thereof having an effective dissolutionprofile.

Another object of the invention is to prepare a sustained release solidoral dosage formulation of phenothiazine derivative and pharmaceuticallyacceptable salt thereof which provides an effective plasma drugconcentration over a prolonged period of time causing a sustained drugaction.

Still a further object of the invention is to develop a sustainedrelease solid oral dosage form of phenothiazine derivatives andpharmaceutical acceptable salt thereof which can be used by a patientonce a day or twice a day, more preferably once a day.

It is a further object of this invention to provide a process for thepreparation of orally administrable sustained release solid oralphenothiazine compound and pharmaceutically acceptable salt thereof witha channelizer.

SUMMARY OF THE INVENTION

The present invention provides a sustained release solid oralpharmaceutical composition(s) and/or dosage form(s) of phenothiazinederivatives, preferably the heterocyclic analogue of phenothiazine, morepreferably the dibenzazepine derivative and most preferably thedibenzothiazepine compound like quetiapine and pharmaceuticallyacceptable salt thereof consisting of a channelizer which acts as a poreforming agent and facilitates the release of active pharmaceuticalingredient from the dosage form through the pores.

DETAILED DESCRIPTION OF THE INVENTION

The present invention describes a sustained release solid oralpharmaceutical formulation containing a phenothiazine derivativepreferably the heterocyclic analogue of phenothiazine, more preferablythe dibenzazepine derivative and most preferably the dibenzothiazepinecompound like quetiapine and pharmaceutical acceptable salt thereof asan active ingredient.

The pharmaceutical formulation of the present invention comprises atablet or capsule as the solid oral dosage form which consist of a coreof active pharmaceutical ingredient with a channelizer, rate controllingpolymer and optionally one or more pharmaceutically acceptableexcipients and a film coating layer surrounding the core.

The formulation of the present invention is preferably based onpreparing core by dry granulation, direct compression, wet granulationmethod or pellet based technology comprising a phenothiazine derivativepreferably the dibenzothiazepine compound like quetiapine or itspharmaceutically acceptable salt.

The uncoated granules are compressed into tablets and then film coatedor the granules/pellets are film coated and then filled into thecapsule.

By the teen sustained release in the present invention it is meant thatthe therapeutically active medicament is released from the formulationat a controlled rate such that the therapeutically effective amount ofactive pharmaceutical ingredient is maintained in the blood plasma overan extended period of time to cause the sustained action of the drug.

In a preferred embodiment, the subject formulation comprises corecovered by film coating layer.

Core comprises of active pharmaceutical ingredient 30-75%, diluent10-80%, channelizer 1-5%, rate controlling polymer10-30%, binder 2-5%,glidant 1-3%, lubricant 2-5% and solvent system.

The active pharmaceutical ingredient is selected from the groupcomprising of phenothiazines derivative. The preferred phenothiazinesderivative is the heterocyclic analogue of phenothiazines, morepreferably dibenzazepines and most preferably the dibenzothiazepinecompound like quetiapine or its pharmaceutically acceptable salt.

Diluent can be selected from the group comprising of but not limited tolactose, sucrose, mannitol, sorbitol, microcrystalline cellulose,calcium phosphates, dextrose, gelatin, acacia, sodium phosphates and thelikes.

Channelizer can be selected from the group comprising of but not limitedto electrolytes (e.g. sodium chloride and the likes), solubleexcipients, osmotic agents, diluents and the likes.

Rate controlling polymers can be selected from the group comprising ofbut not limited to Pyrollidone derivatives, hydroxy propyl methylcellulose, HPC, HEC, MC, Vinyl-acetate copolymers, alginate, xanthangum, guar gum, starch & starch based polymers, poly ethylene oxide,methacrylic acid copolymers, maleic anhydride/methyl vinyl ethercopolymers, ethyl cellulose, cellulose acetate, methacrylates, acrylicacid polymers, poly vinyl acetate, wax and the likes.

Binder can be selected from the group comprising of but not limited topolyvinylpyrollidone, starch, methyl cellulose, ethyl cellulose,polyethylene glycol, polyvinyl alcohol, hydroxypropyl cellulose and thelikes.

Glidants can be selected from the group comprising of but not limited totalc, sodium stearyl fumerate, magnesium stearate, stearic acid, calciumstearate and the likes.

Lubricant can be selected from the group comprising of but not limitedto magnesium stearate, stearic acid, talc, calcium stearate, sodiumstearyl fumerate and the likes.

Solvents are used as per the quantity required and can be selected fromthe group comprising of but not limited to isopropyl alcohol,dichloromethane, methanol, purified water, mixture of likes.

The film coating solution comprises of shellac, zein, hydroxypropylcellulose, hydroxypropyl methylcellulose, ethyl cellulose,polymethacrylates, polyvinyl acetate phthalate, cellulose acetatephthalate, triacetin, dibutyl sebacate, a mixture of polyethyleneglycol, titanium dioxide and hydroxypropyl methylcellulose and thelikes. The film coating solution is in the range of 0.2-4%.

The empty capsule in which the coated granules or pellets are filled canbe selected from hard gelatin capsule, soft gelatin capsule and thelikes.

The dissolution of the active ingredient of the formulation of presentinvention is in 2 hr 10-45%, in 4 hr 15-60%, in 8 hr 25-75%, in 12 hr35-80% , in 18 hr not less than 55% and in 24 hr not less than 65%.

The plasma concentration of the active ingredient after theadministration of solid oral dosage form of the present invention isabove 300 ng/ml between 0.5 to 36 hrs, 300 ng/ml to 3200 ng/ml between 5to 24 hrs and the area under curve (AUC) is not less than 60% to the twoor three immediate release formulations when administered at an intervalof 12 hrs. A single or multiple peak plasma concentration appearsbetween 0.5 hrs to 12 hrs after the administration of the formulation ofthe present invention.

Process for Preparation of Dosage Form:

The manufacturing process of the solid oral dosage form of the presentinvention involves the following steps:

-   -   1. Active pharmaceutical ingredient, diluent, release        controlling polymer, and channelizer are dry mixed to get a        uniform blend.    -   2. Granulation of the blend is done by wet granulation, dry        granulation or direct compression method. The granules are        compressed to form core or the granules are coated with the rate        controlling coating solution and filled into the capsule.    -   3. The compressed core is then film coated using the film        coating solution.

Throughout this specification and the appended claims it is to beunderstood that the words “comprise” and “include” and variations suchas “comprises”, “comprising”, “includes”, “including” are to beinterpreted inclusively, unless the context requires otherwise. That is,the use of these words may imply the inclusion of an element or elementsnot specifically recited.

Example

The present invention has been described by way of example only, and itis to be recognized that modifications thereto falling within the scopeand spirit of the appended claims, and which would be obvious to aperson skilled in the art based upon the disclosure herein, are alsoconsidered to be included within the scope of this invention.

The above said invention can be illustrated by but not limited tofollowing example(s).

TABLE 1 Tablet core: Sr. No. Ingredients % Range Dry Mixing 1.Quetiapine Fumarate 30-75%  2. H.P.M.C K4M 10-30%  3. Lactose 10-80%  4.Sodium Chloride 1-5% Granulation 5. PVP K 30 2-5% 6. Isopropyl AlcoholQ.S. 7. Purified water Q.S. Lubrication 8. Talc 1-3% 9. MagnesiumStearate 2-5%

Procedure:

Weighed quantity of API, rate controlling polymer, diluent andchannelizer are sieved, dry mixed, or granulated with binder solutionand then lubricated. The granules are compressed to form tablet usingrotary compression machine. The tablets are then coated using filmcoating solution described in table-2.

TABLE 2 Film Coating Composition: Sr. No. Ingredients % Range 1.Acryl-eze White 0.2-4% 2. Purified Water Q.S.

Following examples illustrates the compositions of present invention:

TABLE 3 Composition of core tablet Quantity (mg) Ingredient Tablet-1Tablet-2 Tablet-3 Tablet-4 Tablet-5 Tablet-6 Intragranular Quetiapinefumerate 460.54 460.54 460.54 460.54 460.54 460.54 HPMC K4M 101.2 —123.84 123.84 130.72 130.72 HPMC K 100 M — 101.2 — — — —Microcrystalline Cellulose — — 73.99 — 73.99 — Lactose 73.99 73.99 —73.99 — 73.99 Sodium Chloride 18 18 18 18 18 18 Granulation Polyvinylpyrollidone 23 23 23 23 23 23 Isopropyl Alcohol Q.S. Q.S. Q.S. Q.S. Q.S.Q.S. Water Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. Lubrication Talc 9.85 9.85 9.859.85 9.85 9.85 Magnesium Stearate 19.69 19.69 19.69 19.69 19.69 19.69Total 706.27 706.27 728.92 728.92 735.8 735.8

Procedure:

Quetiapine fumarate was mixed with microcrystalline cellulose orlactose, sodium chloride, HPMC K4M or HPMC K100M and granulated withpolyvinyl pyrollidone dissolved in Isopropyl alcohol or/and purifiedwater mixture. The granules were dried, sized, mixed with magnesiumstearate and talc and compressed to form a tablet. The tablets ofexample 1 to 6 are then film coated using coating solution of table-2.

Dissolution Study:

Tablets of examples 1-6 were tested in dissolution studies in a USP Iapparatus in differential pH medium. i.e. 2 hr-0.1 N HCl, 2 hr-Phosphatebuffer pH 5.5 & 20 hr-phosphate buffer pH 6.8. The temperature andagitation were set at 37° C.±0.5° C. and 100 rpm, respectively. Aliquotsof sample were withdrawn at predetermined time intervals and replacedwith an equal amount of fresh media. Samples were processed and suitablyanalyzed. Dissolution profiles of these tablets are given in Table 4.

TABLE 4 Dissolution profiles of tablets of examples 1-6 as measured in aUSP type I apparatus, at 100 rpm, at a temperature of 37° C. ± 0.5° C.in 900 ml of differential pH medium i.e. 2 hr-0.1 N HCL, 2 hr-Phosphatebuffer pH 5.5 & 20 hr-Phosphate buffer pH 6.8. Time % Drug release (Hrs)Tablet 1 Tablet 2 Tablet 3 Tablet 4 Tablet 5 Tablet 6 2 36.4 33.6 30.333.1 30.7 34 4 48.9 44.1 41.3 45.4 42.2 47.3 8 56.1 47.7 45.2 49.5 47.152.9 12 64.3 49.4 50.7 56.9 52.6 60.7 18 73.7 55.8 59.1 65.6 59.6 70.824 78.9 65.8 65.7 71.8 65.9 77.9

1. A once a day sustained release dosage form comprising a phenothiazinederivative or its pharmaceutically acceptable salt, a channelizer forfacilitating release of the phenothiazine derivative or itspharmaceutically acceptable salt from the dosage form through pores thatare formed by the channelizer, a release controlling agent and suitablepharmaceutical excipients.
 2. The dosage form as claimed in claim 1,wherein the phenothiazine derivative is dibenzothiazepine or itsderivative.
 3. The dosage form as claimed in claim 2, wherein thedibenzothiazepine derivative is quetiapine.
 4. The dosage form asclaimed in claim 1, wherein the channelizer is selected fromelectrolytes, soluble excipients, osmotic agents and diluents.
 5. Thedosage form as claimed in claim 1, wherein the release controlling agentcomprises a hydrophilic, a hydrophobic or a swellable polymers or amixture thereof.
 6. The dosage form as claimed in claim 5, wherein thepolymer is selected from the group comprising cellulose derivatives,pyrollidone derivatives, vinyl acetate copolymer, cellulosic acetates,alginates, gums, starch and starch based polymers, methacrylic acidcopolymers, polymethacrylates, maleic anhydride/methyl vinyl ethercopolymers, wax and poly ethylene oxides.
 7. The dosage form as claimedin claim 1, wherein the suitable pharmaceutical excipients are at leastone of a diluent, a binder, a glidant, a lubricant, an anti-adheringagents and a colorants.
 8. The dosage form as claimed in claims 1,wherein the dosage form comprises a core and a film coating solutionsurrounding the core.
 9. The dosage form as claimed in claim 1, whereinthe dissolution profile of the dosage form is 10-45% in 2 hrs, 15-60% in4 hrs, 25-75% in 8 hrs, 35-80% in 12 hrs, not less than 55% in 18 hrsand not less than 65% in 24 hrs.
 10. The dosage form as claimed in claim1, wherein a plasma concentration of the phenothiazine derivative or itspharmaceutically acceptable salt in a subject after administration ofthe dosage form is above 300 ng/ml between 0.5 to 36 hrs, and 300 ng/mlto 3200 ng/ml between 5 to 24 hrs, and the dosage form provides an areaunder curve (AUC) value of the phenothiazine derivative or itspharmaceutically acceptable salt which is not less than 60% of that ofthe same amount if taken as two or three dosages of an immediate releaseformulation at an interval of 12 hours.
 11. The dosage form as claimedin claim 1, wherein after administration of the dosage form to asubject, a single or multiple peak plasma concentration appears between0.5 hrs to 12 hrs.
 12. A once a day sustained release dosage formcomprising quetiapine fumarate in an amount of 55-75% by weight of thedosage form, hydroxy propyl methyl cellulose in an amount of 10-20% byweight of the dosage form, lactose in an amount of 10-25% by weight ofthe dosage form, sodium chloride in an amount of 1-5% by weight of thedosage form, polyvinyl pyrollidone in an amount of 2-5% by weight of thedosage form, magnesium stearate in an amount of 2-5% by weight of thedosage form and talc in an amount of 1-3% by weight of the dosage form.13. The dosage form as claimed in claim 12, wherein a dissolutionprofile of the dosage form is 35-45% in 2 hours, 45-55% in 4 hours,60-70% in 8 hours, 65-75% in 12 hours, 75-85% in 18 hours and not lessthan 80% in 24 hours.
 14. The dosage form as claimed in claims 1,wherein the dosage form comprises granules prepared by a dry granulationmethod or wet granulation method and compressed into a tablet, which isthen film coated.
 15. The dosage form as claimed in claims 1, whereinthe dosage form comprises granules, pellets or coated pellets that aredirectly filled inside a capsule.
 16. (canceled)
 17. The dosage form asclaimed in claim 1, wherein dosage form comprises pellets that are filmcoated and compressed into a tablet with further optional coating. 18.The dosage form as claimed in claim 8, wherein the core comprises thephenothiazine derivative or its pharmaceutically acceptable salt in anamount of 30-75% by weight of the dosage form, diluent in an amount of10-80% by weight of the dosage form, the channelizer in an amount of1-5% by weight of the dosage form, the release controlling agent in anamount of 10-30% by weight of the dosage form, binder in an amount of2-5% by weight of the dosage form, glidant in an amount of 1-3% byweight of the dosage form, and lubricant in an amount of 2-5% by weightof the dosage form, and the film coating solution makes up 0.2-4% byweight of the dosage form.
 19. The dosage form as claimed in claim 12,wherein the dosage form comprises granules that are prepared by a drygranulation method or wet granulation method and compressed into atablet, which is then film coated.
 20. The dosage form as claimed inclaim 12, wherein the dosage form comprises granules, pellets or coatedpellets that are directly filled inside a capsule.
 21. A once a daysustained release dosage form comprising an active pharmaceuticalingredient in an amount of 30-75% by weight of the dosage form, diluentin an amount of 10-80% by weight of the dosage form, pore forming agentin an amount of 1-5% by weight of the dosage form, release controllingagent in an amount of 10-30% by weight of the dosage form, binder in anamount of 2-5% by weight of the dosage form, glidant in an amount of1-3% by weight of the dosage form, lubricant in an amount of 2-5% byweight of the dosage form, and film coating solution in an amount of0.2-4% by weight of the dosage form.
 22. The dosage form as claimed inclaim 21, wherein the dissolution profile of the dosage form is 10-45%in 2 hrs, 15-60% in 4 hrs, 25-75% in 8 hrs, 35-80% in 12 hrs, not lessthan 55% in 18 hrs and not less than 65% in 24 hrs.
 23. The dosage formas claimed in claim 21, wherein a plasma concentration of the activepharmaceutical ingredient in a subject after administration of thedosage form is above 300 ng/ml between 0.5 to 36 hrs, and 300 ng/ml to3200 ng/ml between 5 to 24 hrs and the dosage form provides an areaunder curve (AUC) value of the active pharmaceutical ingredient which isnot less than 60% of that of the same amount if taken as two or threedosages of an immediate release formulation at an interval of 12 hours.24. The dosage form as claimed in claim 21, wherein after administrationof the dosage form to a subject, a single or multiple peak plasmaconcentration appears between 0.5 hrs to 12 hrs.
 25. A treatment methodcomprising using the dosage form of claim 1 to treat a psychotropicdisorder.
 26. A treatment method comprising using the dosage form ofclaim 12 to treat a psychotropic disorder.
 27. A treatment methodcomprising using the dosage form of claim 21 to treat a psychotropicdisorder.
 28. A method of treating a psychotropic disorder comprisingadministering to a mammalian patient in need of a treatment atherapeutically effective amount of the dosage form of claim
 1. 29. Amethod of treating a psychotropic disorder comprising administering to amammalian patient in need of a treatment a therapeutically effectiveamount of the dosage form of claim
 12. 30. A method of treating apsychotropic disorder comprising administering to a mammalian patient inneed of a treatment a therapeutically effective amount of the dosageform of claim 21.